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rdf:type |
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lifeskim:mentions |
umls-concept:C0443211,
umls-concept:C0662760,
umls-concept:C0699794,
umls-concept:C1167622,
umls-concept:C1333653,
umls-concept:C1420805,
umls-concept:C1514562,
umls-concept:C1514873,
umls-concept:C1546857,
umls-concept:C1556066,
umls-concept:C1619636,
umls-concept:C1710082,
umls-concept:C1710548,
umls-concept:C1880389,
umls-concept:C1883204,
umls-concept:C1883221
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pubmed:issue |
11
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pubmed:dateCreated |
2009-11-11
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pubmed:abstractText |
TRAF6 is essential for osteoclastogenesis and for both RANK- and CD40-mediated activation of IKK and MAPKs. RANK, but not CD40, can promote osteoclastogenesis because only RANK induces NFATc1 activation through PLCgamma2-induced Ca(2+) oscillations together with the co-stimulatory signals emanating from immune receptors linked to ITAM-containing adaptors. These previous data suggest that RANK harbors a unique domain that functions in concert with the TRAF6-binding site in osteoclastogenesis. Here we identify such a domain, highly conserved domain in RANK (HCR), which is dispensable for the early phase of RANK and ITAM signaling but is essential for their late-phase signaling, including sustained activation of NF-kappaB and PLCgamma2 leading to NFATc1 activation. HCR recruits an adaptor protein, Gab2, which further associates with PLCgamma2 in the late phase. Formation of the HCR-mediated signaling complex could account for the sustained activation of NF-kappaB and PLCgamma2. The present study identifies HCR as a unique domain that plays a critical role in the long-term linkage between RANK and ITAM signals, providing a molecular basis for therapeutic strategies.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1365-2443
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
14
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1331-45
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pubmed:meshHeading |
pubmed-meshheading:19845770-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:19845770-Amino Acid Sequence,
pubmed-meshheading:19845770-Animals,
pubmed-meshheading:19845770-Antigens, CD40,
pubmed-meshheading:19845770-Cell Differentiation,
pubmed-meshheading:19845770-Conserved Sequence,
pubmed-meshheading:19845770-Humans,
pubmed-meshheading:19845770-Mice,
pubmed-meshheading:19845770-Mice, Inbred C57BL,
pubmed-meshheading:19845770-Models, Biological,
pubmed-meshheading:19845770-Molecular Sequence Data,
pubmed-meshheading:19845770-NFATC Transcription Factors,
pubmed-meshheading:19845770-Osteoclasts,
pubmed-meshheading:19845770-Phospholipase C gamma,
pubmed-meshheading:19845770-Protein Structure, Tertiary,
pubmed-meshheading:19845770-Receptor Activator of Nuclear Factor-kappa B,
pubmed-meshheading:19845770-Sequence Alignment,
pubmed-meshheading:19845770-Signal Transduction,
pubmed-meshheading:19845770-Transcriptional Activation
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pubmed:year |
2009
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pubmed:articleTitle |
A unique domain in RANK is required for Gab2 and PLCgamma2 binding to establish osteoclastogenic signals.
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pubmed:affiliation |
Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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